AU2007207052B2 - CIS-4, 5-biaryl-2-heterocyclic-imidazolines as MDM2 inhibitors - Google Patents

CIS-4, 5-biaryl-2-heterocyclic-imidazolines as MDM2 inhibitors Download PDF

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AU2007207052B2
AU2007207052B2 AU2007207052A AU2007207052A AU2007207052B2 AU 2007207052 B2 AU2007207052 B2 AU 2007207052B2 AU 2007207052 A AU2007207052 A AU 2007207052A AU 2007207052 A AU2007207052 A AU 2007207052A AU 2007207052 B2 AU2007207052 B2 AU 2007207052B2
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bis
chloro
phenyl
dihydro
piperazin
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Nader Fotouhi
Gregory Jay Haley
Klaus B. Simonsen
Binh Thanh Vu
Stephen Evan Webber
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F Hoffmann La Roche AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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Abstract

There are provided compounds of the formula (I), wherein R, V1, V2 and Ring A are described herein. The compounds exhibit anticancer activity.

Description

WO 2007/082805 PCT/EP2007/050136 CIS-4,5-BIARYL-2-HETEROCYCLIC-IMIDAZOLINES AS MDM2 INHIBITORS This invention is related to at least one compound selected from a compound of formula I 5 V1 H N 5 \>-Ring A N H -O V2 R I or the pharmaceutically acceptable salts thereof, wherein V 1 , V 2 , R and ring A are described in this application. These compounds are believed to inhibit the interaction of MDM2 protein with a p53-like peptide and have antiproliferative 10 activity. p53 is a tumor suppresser protein that plays a central role in protection against development of cancer. It guards cellular integrity and prevents the propagation of permanently damaged clones of cells by the induction of growth arrest or 15 apoptosis. At the molecular level, p53 is a transcription factor that can activate a panel of genes implicated in the regulation of cell cycle and apoptosis. p53 is a potent cell cycle inhibitor which is tightly regulated by MDM2 at the cellular level. MDM2 and p53 form a feedback control loop. MDM2 can bind p53 and inhibit its ability to transactivate p53-regulated genes. In addition, MDM2 mediates the 20 ubiquitin-dependent degradation of p53. p53 can activate the expression of the MDM2 gene, thus raising the cellular level of MDM2 protein. This feedback control loop insures that both MDM2 and p53 are kept at a low level in normal proliferating WO 2007/082805 PCT/EP2007/050136 -2 cells. MDM2 is also a cofactor for E2F, which plays a central role in cell cycle regulation. The ratio of MDM2 to p53 (E2F) is dysregulated in many cancers. Frequently 5 occurring molecular defects in the p1 61NK4/p1 9ARF locus, for instance, have been shown to affect MDM2 protein degradation. Inhibition of MDM2-p53 interaction in tumor cells with wild-type p53 should lead to accumulation of p53, cell cycle arrest and/or apoptosis. MDM2 antagonists, therefore, can offer a novel approach to cancer therapy as single agents or in combination with a broad 10 spectrum of other antitumor therapies. The feasibility of this strategy has been shown by the use of different macromolecular tools for inhibition of MDM2-p53 interaction (e.g. antibodies, antisense oligonucleotides, peptides). MDM2 also binds E2F through a conserved binding region as p53 and activates E2F dependent transcription of cyclin A, suggesting that MDM2 antagonists might have 15 effects in p53 mutant cells. Wells et al. J. Org. Chem., 1972, 37, 2158-2161, report synthesis of imidazolines. Hunter et al., Can. J. Chem., 1972, Vol. 50, pgs. 669-77, report the preparation of amarine and isoamarine compounds which had previously been studied for 20 chemiluminescence (McCapra et al. Photochem. and Photobiol. 1965, 4, 1111 1121). Zupanc et al. Bull. Soc. Chem. & Tech. (Yugoslavia) 1980-81, 27/28, 71-80, report the use of triaryl imidazolines as starting materials in the preparation of EDTA derivatives. 25 EP 363 061 to Matsumoto reports imidazoline derivatives useful as immunomodulators. The compounds were indicated to have low toxicity. Treatment and/or prevention of rheumatoid arthritis, multiple sclerosis, systemic lupus, erythemathodes, and rheumatic fever were implicated. WO 00/78725 to Choueiry etal. report a method for making substituted amidine compounds, and 30 indicate that imidazoline-type compounds may be useful in the treatment of diabetes or related diseases involving impaired glucose disposal.
-3 US 6,617,346 B1 (issued September 9, 2003), US 6,734,302 B2 (issued May 11, 2004), US20040259884 Al (published December 23, 2004), US20040259867 Al (published December 23, 2004) disclose related cis-imidazolines. 5 The present invention provides cis-imidazolines which are small molecule inhibitors of the MDM2-p53 interaction. In cell-free and cell-based assays, compounds of the present invention are shown to inhibit the interaction of MDM2 protein with a p53-like peptide. Therefore, the activity of MDM2 antagonists is likely linked to its mechanism of action. These compounds can be potent and selective anticancer agents. 10 In a first aspect the present invention provides the compound of formula I V, H N 5 4 \>Ring A N HO 2 R and the pharmaceutically acceptable salts and esters thereof, wherein 15 Ring A is Xi X 1 Z Y
X
2 wherein
X
1 is ethoxy;
X
2 is hydrogen, -O-(C1-C6)alkyl, -S-(C1-C6)alkyl, -(Cl-C6)alkyl, or -3a
-CF
3 , and Z and Y are both nitrogen;
V
1 and V 2 are -Cl; R is N N
(CH
2 )n wherein
R
1 is oxo, -C(O)-(C1 -6)alkyl, -C(O)-dimethyl isoxazole, -S(0) 2 -(CI-C6)alkyl, or -(C1-C6)alkyl, which is unsubstituted or once substituted by -OH,
-S(O)
2 -(CI-C6)alkyl, -C(O)-morpholino, -C(O)-N[(CI-C6)alkyl} 2 , wherein each alkyl independently is unsubstituted or once substituted by cyano or methoxy, -C(O)-NH-(C1-C6)alkyl, wherein the alkyl is unsubstituted or once substituted by methoxy,
-C(O)-NH
2 , -C(O)-N(CI-C4alkyl)(C1-C4alkoxy), or
-NH-S(O)
2 -(C1-C6)alkyl, and n = 1; and 5 pharmaceutically acceptable salts thereof. Disclosed herein is at least one compound of formula I - 3b VI HN N 4 ~5 \>-~Ring A -~ N HO V2 R and the pharmaceutically acceptable salts and esters thereof, wherein 5 Ring A is: X1 or x Z'&
X
2
X
1 is selected from the group consisting of WO 2007/082805 PCT/EP2007/050136 -4 lower alkoxy, and lower alkoxy substituted by trifluoromethyl or fluorine;
X
2 is selected from the group consisting of 5 hydrogen, thioalkyl, lower alkyl, lower alkoxy, morpholino, and 10 -NX 3
X
4 ;
X
3 and X 4 are independently selected from the group consisting of hydrogen, lower alkyl, 15 lower alkyl substituted by lower alkoxy or cyano, and lower alkoxy; Y and Z are independently selected from the group consisting of: carbon, and 20 nitrogen;
V
1 and V 2 are independently selected from the group consisting of halogen, cyano, and WO 2007/082805 PCT/EP2007/050136 -5 acetylene; R is selected from the group consisting of piperidinyl substituted by five or six membered heterocycle, 5 piperidinyl substituted by -NX 3
X
4 , and * N Ri N ,(CH 2)n wherein 10 n=1 or2,
R
1 can be one or more substituents selected from the group consisting of hydrogen, oxo, 15 lower alkyl substituted by R 2 ,
-C(O)R
3 , and -S0 2 -lower alkyl;
R
2 is selected from the group consisting of 20 hydroxy, lower alkoxy, WO 2007/082805 PCT/EP2007/050136 -6 trifluoromethyl, -cyano, -NH-S0 2 -lower alkyl, -NH-C(O)-lower alkyl, 5 -C(O)-lower alkyl, -C(O)R4,
-C(O)-NX
3
X
4 , -S0 2 -lower alkyl,
-SO
2
-NX
3
X
4 , 10
R
3 is selected from the group consisting of five membered heterocycle, lower alkyl, lower alkoxy, and 15 lower alkyl substituted by lower alkoxy; and
R
4 is selected from the group consisting of hydroxy, lower alkoxy, 20 morpholino, and
-NX
3
X
4 . Preferred compounds are compounds of formula I wherein V 1 and V 2 are each independently selected from -Cl and -Br.
WO 2007/082805 PCT/EP2007/050136 -7 Further preferred compounds are compounds of formula I wherein R is piperazinyl substituted by oxo or lower alkyl substituted by R 2 . 5 Also preferred compounds are compounds in which the two hydrogen atoms of the imidazoline ring are in a cis configuration to each other. The compounds may be in a racemic form and may be optically active. The preferred absolute stereochemistry at the 4 and 5 position of the imidazoline ring are S and R, respectively. 10 Also preferred are the compounds of formula I, wherein Ring A is *S X Sxi Z Y 6
X
2 wherein 15 X 1 is ethoxy;
X
2 is hydrogen, -O-(C1 -C6)alkyl, -S-(C1 -C6)alkyl, -(Cl -C6)alkyl, or 20 -CF 3 , and Z and Y are both nitrogen;
V
1 and V 2 are -Cl; R is WO 2007/082805 PCT/EP2007/050136 -8 * N Ri N ,(CH 2)n wherein
R
1 is oxo, -C(O)-(C1 -6)alkyl, 5 -C(O)-dimethyl isoxazole,
-S(O)
2 -(C1 -C6)alkyl, or -(Cl -C6)alkyl, which is unsubstituted or once substituted by -OH, 10
-S(O)
2 -(C1 -C6)alkyl, -C(O)-morpholino, -C(O)-N[(C1-C6)alkyl] 2 , wherein each alkyl independently is unsubstituted or once substituted by cyano or methoxy, 15 -C(O)-NH-(C1-C6)alkyl, wherein the alkyl is unsubstituted or once substituted by methoxy,
-C(O)-NH
2 , -C(O)-N(C1 -C4alkyl)(C1 -C4alkoxy), or
-NH-S(O)
2 -(C1-C6)alkyl, and 20 n = 1; and pharmaceutically acceptable salts thereof.
-8A In a second aspect the present invention provides a compound according to the first aspect when used as a medicament. In a third aspect the present invention provides a compound according to the first aspect 5 when used for the treatment of cancer. In a fourth aspect the present invention provides the use of a compound according to the first aspect in the manufacture of a medicament for the treatment of cancer. 10 In a fifth aspect the present invention provides a method for the treatment of cancer in a subject in need thereof said method comprising administration to the subject of a therapeutically effective amount of a compound according to the first aspect.
WO 2007/082805 PCT/EP2007/050136 -9 Especially preferred compounds are for example: cis-4-[(4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1 carbonyl]-piperazin-2-one, cis-2-{4-[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole 5 1 -carbonyl]-piperazin-1 -yl}-N,N-dimethyl-acetamide, cis-[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazol-1 -yl] [4-(2-methanesulfonyl-ethyl)-piperazin-1 -yl]-methanone, cis-2-{4-[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole 1 -carbonyl]-piperazin-1 -yl}-1 -morpholin-4-yl-ethanone, 10 cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5 dihydro-imidazole-1 -carbonyl]-piperazin-2-one, cis-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5 dihydro-imidazol-1 -yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1 -yl]-methanone, cis-2-{4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5 15 dihydro-imidazole-1 -carbonyl]-piperazin-1 -yl}-1 -morpholin-4-yl-ethanone, cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro imidazole-1 -carbonyl]-piperazin-2-one, cis-2-{4-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro imidazole-1 -carbonyl]-piperazin-1 -yl}-N,N-dimethyl-acetamide, 20 cis-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro-imidazol 1 -yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1 -yl]-methanone, cis-2-{4-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro imidazole-1 -carbonyl]-piperazin-1 -yl}-1 -morpholin-4-yl-ethanone, cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5 25 dihydro-imidazole-1 -carbonyl]-piperazin-2-one, cis-2-{4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5 dihydro-imidazole-1 -carbonyl]-piperazin-1 -yl}-N,N-dimethyl-acetamide, cis-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5 dihydro-imidazol-1 -yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1 -yl]-methanone, WO 2007/082805 PCT/EP2007/050136 - 10 cis-2-{4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyri midi n-5-yl)-4,5 dihydro-imidazole-1 -carbonyl]-piperazin-1 -yl}-1 -morpholin-4-yl-ethanone, cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyri midi n-5-yl)-4,5-di hydro imidazole-1 -carbonyl]-piperazin-2-one, 5 cis-2-{4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyri midi n-5-yl)-4,5 dihydro-imidazole-1 -carbonyl]-piperazin-1 -yl}-N,N-dimethyl-acetamide, cis-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyri midi n-5-yl)-4,5-di hydro imidazol-1 -yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1 -yl]-methanone, cis-2-{4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyri midi n-5-yl)-4,5 10 dihydro-imidazole-1 -carbonyl]-piperazin-1 -yl}-1 -morpholin-4-yl-ethanone, cis-4-[2-(2-tert-Butyl-4-ethoxy-pyri midi n-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-di hydro imidazole-1-carbonyl]-piperazin-2-one hydrochloride, cis-2-{4-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5 dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide 15 hydrochloride, cis-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride, cis-2-{4-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5 20 dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-l-morpholin-4-yl-ethanone, cis-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazol-1-yl]-(4-dimethylamino-piperidin-1-yl)-methanone, cis-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone, 25 cis-1 -{4-[2-(2-tert-Butyl-4-ethoxy-pyri midi n-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5 dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethanone, cis-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone, cis-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro 30 imidazol-1-yl]-[4-(3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone, WO 2007/082805 PCT/EP2007/050136 - 11 cis-[2-(2-tert-Butyl-4-ethoxy-pyri midi n-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-di hydro imidazol-1 -yl]-[4-(2-hydroxy-ethyl)-piperazin-1 -yl]-methanone, 2-{4-[(4S,5 R)-2-(2-tert-Butyl-4-ethoxy-pyri midi n-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5 dihydro-imidazole-1 -carbonyl]-piperazin-1 -yl}-1 -morpholin-4-yl-ethanone, 5 4-[(4S,5R)-2-(2-tert-Butyl-4-ethoxy-pyri midi n-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5 dihydro-imidazole-1 -carbonyl]-piperazin-2-one, cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4,6-diethoxy-pyridin-3-yl)-4,5-dihydro-imidazole 1-carbonyl]-piperazin-2-one hydrochloride, cis-[4,5-Bis-(4-chloro-phenyl)-2-(4,6-diethoxy-pyridin-3-yl)-4,5-dihydro-imidazol-1 10 yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone hydrochloride, 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1 -carbonyl]-piperazin-1 -yl}-N-tert-butyl-acetamide, 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1 -carbonyl]-piperazin-1 -yl}-acetamide, 15 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1 -carbonyl]-piperazin-1 -yl}-N,N-bis-(2-methoxy-ethyl)-acetamide, 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1 -carbonyl]-piperazin-1 -yl}-N-methoxy-N-methyl-acetamide, 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro 20 imidazole-1 -carbonyl]-piperazin-1 -yl}-N-isopropyl-N-methyl-acetamide, 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1 -carbonyl]-piperazin-1 -yl}-N-(2-cyano-ethyl)-N-methyl-acetamide, cis-2-{4-[4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1 -carbonyl]-piperazin-1 -yl}-N-(2-methoxy-1 -methyl-ethyl)-acetamide, 25 [(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazol 1 -yl]-[4-(3,5-dimethyl-isoxazole-4-carbonyl)-piperazin-1 -yl]-methanone, [(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazol 1 -yl]-(4-ethanesulfonyl-piperazin-1 -yl)-methanone, N-(2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro 30 imidazole-1-carbonyl]-piperazin-1-yl}-ethyl)-methanesulfonamide, WO 2007/082805 PCT/EP2007/050136 - 12 [(4S,5 R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-di hydro-i midazol 1 -yl]-[4-(3-methanesulfonyl-propyl)-piperazin-1 -yl]-methanone, [(4S,5 R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-di hydro-i midazol 1 -yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1 -yl]-methanone and 5 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1 -carbonyl]-piperazin-1 -yl}-1 -morpholin-4-yl-ethanone. "Effective amount" means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being 10 treated. "Halogen" means fluorine, chlorine, bromine or iodine. "Hetero atom" means an atom selected from N, 0 and S. 15 "IC50" refers to the concentration of a particular compound required to inhibit 50% of a specific measured activity. IC50 can be measured, inter alia, as is described subsequently. 20 "Alkyl" denotes a straight-chained or branched saturated aliphatic hydrocarbon. Preferably such "alkyl" consists of 14, more preferably of 12, most preferred of 8 carbon-atoms. "Cycloalkyl" means a non-aromatic, partially or completely saturated monovalent 25 cyclic hydrocarbon radical containing 3 to 8 atoms. Preferred examples of cycloalkyl groups are cyclopropyl, cyclobutyl, and cyclopentyl. "Five or six membered heterocycle" means an aromatic or non-aromatic, 5 or 6 membered cyclic hydrocarbon wherein one to three, preferably one or two carbon- WO 2007/082805 PCT/EP2007/050136 - 13 atoms are replaced by hetero-atoms independently selected from oxygen, nitrogen or sulfur. Preferred examples of five or six membered heterocycles include, but are not limited to pyrrolidine, pyrazolidine, imidazolidine, imidazole, pyrazole, triazole, oxazolidine, isoxazolidine, oxazole, isoxazole, thiazolidine, piperidine, piperazine, 5 morpholine and the like. "Lower alkyl" groups denote C1-C6 alkyl groups and include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl, and the like. Generally, lower alkyl is preferably C1-C4 alkyl, and more preferably C1-C3 alkyl. 10 "Alkoxy" denotes -0-alkyl. "Lower alkoxy" denotes -0-lower alkyl. "Pharmaceutically acceptable ester" refers to a conventionally esterified compound of formula I having a carboxyl group, which esters retain the biological effectiveness and properties of the compounds of formula I and are cleaved in vivo 15 (in the organism) to the corresponding active carboxylic acid. Information concerning esters and the use of esters for the delivery of pharmaceutical compounds is available in Design of Prodrugs, Bundgaard H ed. (Elsevier, 1985). See also, H. Ansel etal., Pharmaceutical Dosage Forms and 20 Drug Delivery Systems (6th Ed. 1995) at pp. 108-109; Krogsgaard-Larsen, et al., Textbook of Drug Design and Development (2d Ed. 1996) at pp. 152-191. "Pharmaceutically acceptable salt" refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the 25 compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, 30 salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. Chemical WO 2007/082805 PCT/EP2007/050136 - 14 modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., H. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 5 1995) at pp. 196 and 1456-1457; or Richard J. Bastin et al, Organic Process Research & Development 2000, 4, 427-435. "Pharmaceutically acceptable," such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to 10 the subject to which the particular compound is administered. "Substituted" means that the substitution can occur at one or more positions and, unless otherwise indicated, that the substituents at each substitution site are independently selected from the specified options. 15 "Therapeutically effective amount" means an amount of at least one designated compound, that significantly inhibits proliferation and/or prevents differentiation of a human tumor cell, including human tumor cell lines. 20 Compounds of the present invention as exemplified advantageously show IC50s from about 0.030 uM to about 7 uM. The compounds of the present invention are useful in the treatment or control of cell proliferative disorders, in particular oncological disorders. These compounds 25 and formulations containing said compounds may be useful in the treatment or control of solid tumors, such as, for example, breast, colon, lung and prostate tumors. A therapeutically effective amount of a compound in accordance with this invention 30 means an amount of compound that is effective to prevent, alleviate or ameliorate WO 2007/082805 PCT/EP2007/050136 - 15 symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art. The therapeutically effective amount or dosage of a compound according to this 5 invention can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing 10 approximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion. 15 The present invention also provides pharmaceutical compositions comprising at least one compound of formula I, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier or excipient. 20 The compounds of the present invention can be prepared according to the following scheme 1, wherein unless explicitly otherwise stated, all substituents, variables, reactants or agents have the meanings given herein before or are well known to the person of ordinary skill in the art.
WO 2007/082805 PCT/EP2007/050136 - 16 Scheme I MeO 0 crX1 Y Z X2 | H NHR AIMe 3 N + OR Al , \ Ring A
NH
2 N Et O H H V 1 V 2 S X1 Phosgene 2 V1 V IH H N 1. R amine group N \>-Ring A :-Ring A N 2. Chiral Separation N H (optional) H O H
V
2 R V 2 CI racemic-4 R amine group Chiral Separation V1 (optional) V1V1 HH N N \>-Ring A + \>-Ring A N N V CI V - CI enant-5A 2 enant-5B The synthesis commences with the coupling reaction of the ester 2 with meso-1,2 bis-(4-chlorophenyl)-ethane-1,2-diamine 1 (prepared according to the procedure 5 described by Jennerwein, M. et al. Cancer Res. Clin. Oncol. 1988, 114, 347-58; Vogtle, F.; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40) using trimethylaluminum as a catalyst in a solvent such as toluene with heating at reflux (Moormann, A. E. et al J. Med. Chem. 1990, 33, 614-626). The esters 2 are prepared using the procedures known in the art. Treatment of the imidazoline 3 with phosgene in the 10 presence of a base such as triethylamine gives the racemic carbamoyl chloride 4. Coupling of the racemic carbamoyl chloride 4 with appropriate R amine groups provides the compounds of the formula I as racemic mixtures. Many R amine groups are commercially available. If it is desired, R amine groups can be WO 2007/082805 PCT/EP2007/050136 - 17 prepared using synthetic methods known in the art. Suitable processes for making these R amine groups are provided in the examples. If it is desired to prepare the optically active compounds of formula I, the 5 enantiomers of the carbamoyl chloride rac-4 can be separated using chiral chromatography. The chiral stationary phase R,R-Whelk-01, available through Regis Technologies, can be used. Coupling of the desired enantiomer 5A with appropriate R amine groups provides the optically active compounds of the formula I. 10 Also the optically active compounds of formula I can be obtained by chiral separation of the racemic mixtures of I. The chiral stationary phase Diacel ChiralPak OD or AD can be used. 15 The absolute stereochemistry of the preferred enantiomer of I is determined based on the crystal structure of its complex with the human MDM2 (Vassilev et al. Science, 2004, 303, 844-848. The following examples and references are provided to aid the understanding of 20 the present invention, the true scope of which is set forth in the appended claims.
WO 2007/082805 PCT/EP2007/050136 - 18 Example 1 cis-4-[(4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-vridin-3-vl)-4,5-dihydro-imidazole-1 5 carbonyll-piperazin-2-one H N H O K -N
H
0 To a solution of 2-chloronicotinic acid (5 g, 31.7 mmol, Aldrich) in dimethylformamide (50 mL) were added potassium carbonate (6.579 g, 47.6 mmol) and ethyl iodide (3.8 mL, 47.7 mmol), respectively. The reaction mixture 10 was stirred at room temperature for 3 d. Water (~50 mL) was added and the product was extracted with ethyl ether (2 x 75 mL). The combined organic phases were washed with brine (1 x 50 mL), dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated under reduced pressure to give 2-chloronicotinic acid ethyl ester as yellow oil. It was then 15 dissolved in ethanol (50 mL) and sodium ethoxide (17.8 mL, 47.6 mmol, 21% in ethanol, Aldrich) was added dropwise. Precipitation was seen as sodium ethoxide was added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated and the residue partitioned between methylene chloride (150 mL) and water (50 mL). The aqueous layer was extracted with 20 methylene chloride (1 x 50 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (120 g of silica gel, 10-30% ethyl acetate in hexane) to give 2-ethoxynicotinic acid ethyl ester as an orange oil (4.04 g, 65% yield for 2 steps). 25 Trimethylaluminum (1.156 mL, 2.312 mmol, 2 M solution in toluene, Aldrich) was added to a flask via syringe and cooled to 0 OC. A mixture of meso-1,2-bis-(4 chlorophenyl)-ethane-1,2-diamine (650 mg, 2.312 mmol, prepared according to the procedure described by Jennerwein, M. et al. Cancer Res. Clin. Oncol. 1988, WO 2007/082805 PCT/EP2007/050136 - 19 114, 347-58; Vogtle, F.; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40) in about 8 mL of toluene was added dropwise over a period of 30 min. After the addition was completed, the cooling bath was removed, and the mixture was stirred at room temperature for 15 min, at 50-60 OC for 30 min, and then at 80-90 OC for 30 min. 5 When the temperature was cooled back to 60 OC, a solution of 2-ethoxynicotinic acid ethyl ester (418.9 mg, 2.312 mmol) in toluene (5 mL) was added. The reaction mixture was heated at reflux for 2 h. The reaction mixture was then cooled in ice bath to 10 C, and 1 M Rochelle salt solution (10 mL) was added. The ice bath was removed, and the biphasic mixture was stirred vigorously for 30 10 min. Ethyl acetate (20 mL) was added and stirring was continued overnight. The layers were separated, and the organic layer was washed with brine (1x) and dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo to give a yellow oil (950 mg). The crude product was purified by flash chromatography (40 g, eluting with 15% ethyl acetate in hexane, 15 50% ethyl acetate in hexane, then ethyl acetate) to give 4,5-bis-(4-chloro-phenyl) 2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-1 H-imidazole as white solids (481 mg, 51 %). To a solution of 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-1H imidazole (475 mg, 1.152 mmol) and triethylamine (321 uL, 2.304 mmol) in 20 methylene chloride (6 mL) cooled to 0 OC was added phosgene (895 uL, 1.728 mmol, 20% solution in toluene, Fluka). The reaction mixture was stirred at 0 OC for 30 min then concentrated to dryness. The residue was taken in ethyl acetate, and the solids were filtered off. The filtrate was concentrated to give crude 4,5-bis-(4 chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl chloride 25 as yellow solids (450 mg). To a solution of 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro imidazole-1-carbonyl chloride (100 mg, 0.211 mmol) in methylene chloride (3 mL) at room temperature were added triethylamine (88 uL) and 2-piperazinone (31.7 30 mg, 0.317 mmol, Tyger Scientific), respectively. The reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by thin layer chromatography (silica gel, 15% methanol in ethyl acetate). The reaction mixture was concentrated to dryness, and the crude residue was purified by high performance liquid chromatography (C18-silica gel, eluting with a gradient of 5 35 95% acetonitrile in water) to give cis-4-[(4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy pyridin-3-yl)-4,5-dihydro-imidazole-1 -carbonyl]-piperazin-2-one as white solid (98 WO 2007/082805 PCT/EP2007/050136 - 20 mg, 86%). HR-MS (ES, m/z) calculated for C 27
H
26
N
5
O
3 Cl 2 [(M+H)*] 538.1407, observed 538.1408. Example 2 5 cis-2-{4-[4,5-Bis-(4-chloro-phenvl)-2-(2-ethoxy-pvridin-3-yl)-4,5-dihydro-imidazole 1 -carbonyll-piperazin-1 -yl}-NN-dimethyl-acetamide CI H N -N H O N 0N -N 4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1 10 carbonyl chloride (example 1) was reacted with N,N-dimethyl-2-piperazin-1-yl acetamide (Oakwood Products) to give cis-2-{4-[4,5-bis-(4-chloro-phenyl)-2-(2 ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1 -carbonyl]-piperazin-1 -yl}-N,N dimethyl-acetamide in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C31 H 3 5
N
6 0 3
CI
2 [(M+H)*] 609.2142, observed 609.2146. 15 Example 3 cis-[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxv-pvridin-3-yl)-4,5-dihydro-imidazol-1 -VIl [4-(2-methanesulfonyl-ethyl)-piperazin-1 -yll-methanone C~ 4H H H )= / N C II N -N N ClO r-J 20I WO 2007/082805 PCT/EP2007/050136 - 21 Methyl vinyl sulfone (1.8 mL, 20.1 mmol) was added to a solution of 1-(tert butyloxycarbonyl)piperazine (1.50 g, 8 mmol) in methanol (84 mL). The reaction mixture was stirred at room temperature for 4 h and concentrated to a white solid. Purification of the solid by flash column chromatography (silica gel, eluting with 1 5 5% methanol in methylene chloride) gave 1-tert-butyloxycarbonyl-4-(2 methanesulfonylethyl)piperazine as a white solid (2.29 g, 95%). Hydrochloric acid (42 mL, 168 mmol, 4 M in 1,4-dioxane) was added to a cooled solution of 1-tert-butyloxycarbonyl-4-(2-methanesulfonylethyl)piperazine (2.29 g, 10 7.8 mmol) in 1,4-dioxane (42 mL). The mixture was stirred at room temperature overnight then concentrated to give 1-(2-methanesulfonylethyl)piperazine dihydrochloride as a white solid (2.05 g). 4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1 15 carbonyl chloride (example 1) was reacted with 1-(2 methanesulfonylethyl)piperazine dihydrochloride to give cis-[4,5-bis-(4-chloro phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazol-1 -yl]-[4-(2-methanesulfonyl ethyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C 3 0
H
34
N
5 04SC1 2 [(M+H)*] 630.1703, observed 20 603.1705. Example 4 cis-2-{4-[4,5-Bis-(4-chloro-phenvl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole 25 1 -carbonyll-piperazin-1 -yl}-1 -morpholin-4-yl-ethanone H. N H N N ci ) N
O
WO 2007/082805 PCT/EP2007/050136 - 22 4,5- Bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1 carbonyl chloride (example 1) was reacted with 1-morpholin-4-yl-2-piperazin-1-yl ethanone (Oakwood Products) to give cis-2-{4-[4,5-bis-(4-chloro-phenyl)-2-(2 ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1 -carbonyl]-piperazin-1-yl}-l-morpholin 5 4-yl-ethanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C 33
H
37
N
6 04CI 2 [(M+H)*] 651.2248, observed 651.2250. Example 5 10 cis-4-[4,5-Bis-(4-chloro-iphenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5 dihydro-imidazole-1 -carbonyll-piperazin-2-one HN N -N FF H )=O N NCNF H 4-Hydroxy-2-trifluoromethyl-pyrimidine-5-carboxylic acid (1 g, 4.828 mmol, 15 Oakwood Products) was dissolved in dimethylformamide (10 mL) and potassium carbonate (1.668 g, 12.070 mmol) was added. After stirring at room temperature for 15 min, iodoethane (0.966 mL, 12.070 mmol) was added and the reaction mixture was stirred at room temperature for 3 d. Water was added, and the product was extracted with ethyl acetate (2x). The organic layers were washed 20 with water (1x), brine (1x) and dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, eluting with a gradient of 5 50% ethyl acetate in hexanes) to give 4-ethoxy-2-trifluoromethyl-pyrimidine-5 carboxylic acid ethyl ester (852 mg, 67%). 25 4-Ethoxy-2-trifluoromethyl-pyrimidine-5-carboxylic ethyl ester was reacted with meso-1,2-bis-(4-chlorophenyl)-ethane-1,2-diamine in an analogous manner as described in example 1 to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2- WO 2007/082805 PCT/EP2007/050136 - 23 trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro-1 H-imidazole. HR-MS (ES, m/z) calculated for C 22
H
18
N
4 0F 3
CI
2 [(M+H)*] 481.0805, observed 481.0806. Using the procedure as described in example 1, cis-4-[4,5-bis-(4-chloro-phenyl)-2 5 (4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro-1H-imidazole was reacted with phosgene to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2 trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride. The carbonyl chloride was then coupled with 2-piperazinone to give cis-4-[4,5-bis-(4 chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro-imidazole 10 1 -carbonyl]-piperazin-2-one. HR-MS (ES, m/z) calculated for C 27
H
24
N
6 0 3
F
3 CI2 [(M+H)*] 607.1234, observed 607.1231. Example 6 15 cis-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pvrimidin-5-yl)-4,5 dihydro-imidazol-1 -vll-[4-(2-methanesulfonyl-ethyl)-piperazin-1 -yll-methanone CI H N HO NH -= N FF N N ci cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5 dihydro-imidazole-1 -carbonyl chloride (example 5) was reacted with 1-(2 20 methanesulfonylethyl)piperazine dihydrochloride (example 3) to give cis-[4,5-bis (4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for
C
3 0
H
32
N
6 04SF 3
CI
2 [(M+H)*] 699.1530, observed 699.1533. 25 WO 2007/082805 PCT/EP2007/050136 - 24 Example 7 cis-2-{4-[4,5-Bis-(4-chloro-phenvl)-2-(4-ethoxy-2-trifluoromethyl-pvrimidin-5-yl)-4,5 5 dihydro-imidazole-1 -carbonyll-piperazin-1 -yl}-1 -morpholin-4-yl-ethanone ci HN H. N 0-N F H O N ci C N (7 N cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5 dihydro-imidazole-1 -carbonyl chloride (example 5) was reacted with 1 -morpholin 4-yl-2-piperazin-1 -yl-ethanone (Oakwood Products) to give cis-2-{4-[4,5-bis-(4 10 chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro-imidazole 1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C 33
H
35
N
7 0 4
F
3
CI
2 [(M+H)*] 720.2074, observed 720.2075. 15 Example 8 cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pvrimidin-5-yl)-4,5-dihydro imidazole-1 -carbonyll-piperazin-2-one H N N H O C1 N H O
H
0 20 To a solution of ethyl 4-chloro-5-pyrimidine carboxylate (5 g, 21.488 mmol, Aldrich) in ethanol (50 mL) was added sodium ethoxide dropwise (12 mL, 32.232 mmol, WO 2007/082805 PCT/EP2007/050136 - 25 21% solution in ethanol, Aldrich). Precipitation was seen as sodium ethoxide was added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then heated at ~60 OC for 2 h. The reaction mixture was then diluted with ethyl acetate, washed with water, brine, and dried over magnesium 5 sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (120 g of silica gel, gradient of 10 50% ethyl acetate in hexane) to give 2,4-diethoxy-pyrimidine-5-carboxylic ethyl ester (1.679 g) and 4-ethoxy-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.764 g). 10 2,4- Diethoxy-pyrimidine-5-carboxylic ethyl ester was reacted with meso-1,2-bis (4-chlorophenyl)-ethane-1,2-diamine in an analogous manner as described in example 1 to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl) 4,5-dihydro-1 H-imidazole. HR-MS (ES, m/z) calculated for C 23
H
23
N
4 0 2
CI
2 [(M+H)*] 15 457.1193, observed 457.1193. Using the procedure as described in example 1, cis-4-[4,5-bis-(4-chloro-phenyl)-2 (2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro-1 H-imidazole was reacted with phosgene to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro 20 imidazole-1-carbonyl chloride. The carbonyl chloride was then coupled with 2 piperazinone (Alfa) to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(2,4-diethoxy pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one. HR-MS (ES, m/z) calculated for C2 8
H
29
N
6 04CI 2 [(M+H)*] 583.1622, observed 583.1621.
WO 2007/082805 PCT/EP2007/050136 - 26 Example 9 cis-2-{4-[4,5-Bis-(4-chloro-phenvl)-2-(2,4-diethoxv-pvrimidin-5-yl)-4,5-dihydro 5 imidazole-1-carbonyll-piperazin-1-yl}-NN-dimethyl-acetamide Cl H -N H O N N -N cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro imidazole-1-carbonyl chloride (example 8) was reacted with N,N-dimethyl-2 piperazin-1 -yl-acetamide (Oakwood Products) to give cis-2-{4-[4,5-bis-(4-chloro 10 phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl] piperazin-1 -yl}-N,N-dimethyl-acetamide in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C 32
H
37
N
7 0 4
CI
2 [(M+H)*] 654.2357, observed 654.2355. 15 Example 10 cis-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pvrimidin-5-yl)-4,5-dihydro-imidazol 1 -vll-[4-(2-methanesulfonyl-ethyl)-piperazin-1 -yll-methanone SN N H )O N f-i oDzS cl WO 2007/082805 PCT/EP2007/050136 - 27 cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyri midi n-5-yl)-4,5-di hydro imidazole-1-carbonyl chloride (example 8) was reacted with 1-(2 methanesulfonylethyl)-piperazine dihydrochloride (example 3) to give cis-[4,5-bis (4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro-imidazol-1 -yl]-[4-(2 5 methanesulfonyl-ethyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C 31
H
37
N
6 0 5 SC1 2 [(M+H)*] 675.1918, observed 675.1914. Example 11 10 cis-2-{4-[4,5-Bis-(4-chloro-phenvl)-2-(2,4-diethoxy-pvrimidin-5-yl)-4,5-dihydro imidazole-1 -carbonyll-piperazin-1 -yl}-1 -morpholin-4-yl-ethanone CI ciH N -N 0 N \H \,FO CI y 0N N 0 cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro 15 imidazole-1-carbonyl chloride (example 8) was reacted with 1-morpholin-4-yl-2 piperazin-1 -yl-ethanone (Oakwood Products) to give cis-2-{4-[4,5-bis-(4-chloro phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro-imidazole-1 -carbonyl] piperazin-1-yl}-1-morpholin-4-yl-ethanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C 34
H
4 oN 7 0 5
CI
2 [(M+H)*] 696.2463, 20 observed 696.2463.
WO 2007/082805 PCT/EP2007/050136 - 28 Example 12 cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pvrimidin-5-yl)-4,5 5 dihydro-imidazole-1-carbonyll-piperazin-2-one CI N N N H O N H 0 4-Ethoxy-2-methylsulfanyl-pyri midi ne-5-carboxylic acid ethyl ester (example 8) was reacted with meso-1 ,2-bis-(4-chlorophenyl)-ethane-1 ,2-diamine in an analogous manner as described in example 1 to give cis-4-[4,5-bis-(4-chloro 10 phenyl)-2-(4-ethoxy-2-methyl-sulfanyl-pyri midin-5-yl)-4,5-di hydro-1 H-i midazole. HR-MS (ES, m/z) calculated for C 22
H
21
N
4 0SCI 2 [(M+H)*] 459.0808, observed 459.0808. Using the procedure as described in example 1, cis-4-[4,5-bis-(4-chloro-phenyl)-2 15 (4-ethoxy-2-methylsulfanyl-pyri midi n-5-yl)-4,5-di hydro-1 H-i midazole was reacted with phosgene to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2 methylsulfanyl-pyri midin-5-yl)-4,5-di hydro-i midazole-1 -carbonyl chloride. The carbonyl chloride was then coupled with 2-piperazinone (Alfa) to give cis-4-[4,5 bis-(4-ch loro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyri midi n-5-yl)-4,5-di hydro 20 imidazole-1-carbonyl]-piperazin-2-one. HR-MS (ES, m/z) calculated for
C
27
H
27
N
6
O
3
SCI
2 [(M+H)*] 585.1237, observed 585.1236.
WO 2007/082805 PCT/EP2007/050136 - 29 Example 13 cis-2-{4-[4,5-Bis-(4-chloro-phenvl)-2-(4-ethoxy-2-methylsulfanyl-pvrimidin-5-yl)-4,5 5 dihydro-imidazole-1-carbonyll-piperazin-1-yl}-NN-dimethyl-acetamide ci H N -N H O N 1ci -N\ cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5 dihydro-imidazole-1-carbonyl chloride (example 12) was reacted with N,N dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) to give cis-2-{4-[4,5-bis 10 (4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro imidazole-1 -carbonyl]-piperazin-1 -yl}-N,N-dimethyl-acetamide in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C31 H 36
N
7 0 3 SC1 2 [(M+H)*] 656.1972, observed 656.1973. 15 Example 14 cis-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5 dihydro-imidazol-1 -vll-[4-(2-methanesulfonyl-ethyl)-piperazin-1 -yll-methanone ci JH 0 N -N N N H O N ci o szo
N
WO 2007/082805 PCT/EP2007/050136 - 30 cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsu Ifanyl-pyri midi n-5-yl)-4,5 dihydro-imidazole-1-carbonyl chloride (example 12) was reacted with 1-(2 methanesulfonylethyl)-piperazine dihydrochloride (example 3) to give cis-[4,5-bis (4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro 5 imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for
C
3 0
H
3 5
N
6 04S2CI 2 [(M+H)*] 677.1533, observed 677.1532. Example 15 10 cis-2-{4-[4,5-Bis-(4-chloro-phenvl)-2-(4-ethoxy-2-methylsulfanyl-pvrimidin-5-yl)-4,5 dihydro-imidazole-1 -carbonyll-piperazin-1-yl}-1 -morpholin-4-yl-ethanone H N N -N N ci ) 0N 0 cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5 15 dihydro-imidazole-1-carbonyl chloride (example 12) was reacted with 1-morpholin 4-yl-2-piperazin-1 -yl-ethanone (Oakwood Products) to give cis-2-{4-[4,5-bis-(4 chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro-imidazole 1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C 33
H
38
N
7 0 4 SC1 2 [(M+H)*] 20 698.2078, observed 698.2078.
WO 2007/082805 PCT/EP2007/050136 - 31 Example 16 cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pvrimidin-5-yl)-4,5-dihydro 5 imidazole-1-carbonyll-piperazin-2-one SN H N -N N N SH /N CIN H 0 4-Ethoxy-2-methyl-pyrimidine-5-carboxylic acid ethyl ester (prepared according to the procedures described by Baxter, R. L. et al. J. Chem. Soc. Perkin Trans. / 10 1990, 2963-2966 and Dostert, P. et al. Eur. J. Med. Chem. 1982, 17, 437-444) was reacted with meso-1,2-bis-(4-chlorophenyl)-ethane-1,2-diamine in an analogous manner as described in example 1 to give cis-4-[4,5-bis-(4-chloro phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-1 H-imidazole. HR-MS (ES, m/z) calculated for C 22
H
2 1
N
4 0SC1 2 [(M+H)*] 459.0808, observed 459.0808. 15 Using the procedure as described in example 1, cis-4-[4,5-bis-(4-chloro-phenyl)-2 (4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-1 H-imidazole was reacted with phosgene to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin 5-yl)-4,5-dihydro-imidazole-1 -carbonyl chloride. The carbonyl chloride was then 20 coupled with 2-piperazinone (Alfa) to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4 ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1 -carbonyl]-piperazin-2-one. HR-MS (ES, m/z) calculated for C 27
H
27
N
6 03CI 2 [(M+H)*] 553.1516, observed 553.1515.
WO 2007/082805 PCT/EP2007/050136 - 32 Example 17 cis-2-{4-[4,5-Bis-(4-chloro-phenvl)-2-(4-ethoxy-2-methvl-pvrimidin-5-yl)-4,5 5 dihydro-imidazole-1-carbonyll-piperazin-1-yl}-NN-dimethyl-acetamide Cl H N0 NN H ON N cl N )= -N cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro imidazole-1-carbonyl chloride (example 16) was reacted with N,N-dimethyl-2 piperazin-1 -yl-acetamide (Oakwood Products) to give cis-4-[4,5-bis-(4-chloro 10 phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl] piperazin-1 -yl}-N,N-dimethyl-acetamide in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C 31
H
36
N
7 0 3
CI
2 [(M+H)*] 624.2251, observed 624.2253. 15 Example 18 cis-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methvl-pvrimidin-5-yl)-4,5-dihydro imidazol-1-vll-[4-(2-methanesulfonyl-ethyl)-piperazin-1-vll-methanone N N N N H O N cl N I-0 WO 2007/082805 PCT/EP2007/050136 - 33 cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyri midi n-5-yl)-4,5-di hydro imidazole-1-carbonyl chloride (example 16) was reacted with 1-(2 methanesulfonyl-ethyl)piperazine dihydrochloride (example 3) to give cis-[4,5-bis (4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-imidazol-1-yl] 5 [4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C 3 0
H
34
N
6 04SC1 2 [(M+H)*] 645.1812, observed 645.1814. Example 19 10 cis-2-{4-[4,5-Bis-(4-chloro-phenvl)-2-(4-ethoxy-2-methvl-pvrimidin-5-yl)-4,5 dihydro-imidazole-1 -carbonyll-piperazin-1-yl}-1 -morpholin-4-yl-ethanone H N N N4 N \H =O ci ) N 0 O 15 cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro imidazole-1-carbonyl chloride (example 16) was reacted with 1-morpholin-4-yl-2 piperazin-1 -yl-ethanone (Oakwood Products) to give cis-2-{4-[4,5-bis-(4-chloro phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl] piperazin-1-yl}-1-morpholin-4-yl-ethanone in an analogous manner as described in 20 example 1. HR-MS (ES, m/z) calculated for C 33
H
38
N
7 0 4
CI
2 [(M+H)*] 666.2357, observed 666.2358.
WO 2007/082805 PCT/EP2007/050136 - 34 Example 20 cis-4-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-p~henyl)-4,5-dihydro 5 imidazole-1-carbonyll-piperazin-2-one hydrochloride CI H O N -N N N N H O CIH A solution of 4-hydroxy-2-tert-butyl-pyrimidine-5-carboxylic acid ethyl ester (3 g, 13.377 mmol, prepared in an analogous manner as described for the preparation of 2-ethyl-4-hydroxy-pyrimidine-5-carboxylic acid ethyl ester, Dostert, P. et al. Eur. 10 J. Med. Chem. 1982, 17, 437-444) in dimethylformamide (10 mL) was added slowly to the suspension of sodium hydride (800 mg, 60% in mineral oil, Aldrich) in dimethylformamide cooled to 0 OC. After the addition, the icebath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was stirred at room temperature for 4 h then quenched with saturated 15 solution of ammonium chloride. It was extracted with ethyl acetate (2x). The organic extracts were washed with brine (1x), dried over anhydrous sodium sulfate and concentrated. Purification of the crude residue by flash column chromatography (120 g of silica gel, eluting with a gradient of 5-60% ethyl acetate in hexane gave 4-ethoxy-2-tert-butyl-pyrimidine-5-carboxylic acid ethyl ester (1.12 20 g, 30%). 2-tert-Butyl-4-ethoxy-pyrimidine-5-carboxylic acid ethyl ester was reacted with meso-1,2-bis-(4-chlorophenyl)-ethane-1,2-diamine in an analogous manner as described in example 1 to give cis-4-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5 25 bis-(4-chloro-phenyl)-4,5-dihydro-1 H-imidazole. HR-MS (ES, m/z) calculated for
C
22
H
21
N
4 0SC1 2 [(M+H)*] 459.0808, observed 459.0808. Using the procedure as described in example 1, cis-4-[2-(2-tert-butyl-4-ethoxy pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazole was reacted WO 2007/082805 PCT/EP2007/050136 - 35 with phosgene to give cis-4-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4 chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride. The carbonyl chloride was then coupled with 2-piperazinone (Alfa) to give cis-4-[2-(2-tert-butyl-4-ethoxy pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1 -carbonyl] 5 piperazin-2-one hydrochloride. HR-MS (ES, m/z) calculated for C 30
H
3 3
N
6 0 3
CI
2 [(M+H)*] 595.1986, observed 595.1985. Example 21 10 cis-2-{4-[2-(2-tert-Butyl-4-ethoxy-ipyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5 dihydro-imidazole-1 -carbonyll-piperazin-1 -yl}-NN-dimethyl-acetamide hydrochloride CI IH O N N HN N N CIH cis-4-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro 15 imidazole-1-carbonyl chloride (example 20) was reacted with N,N-dimethyl-2 piperazin-1 -yl-acetamide (Oakwood Products) to give cis-2-{4-[2-(2-tert-butyl-4 ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1 -carbonyl] piperazin-1-yl}-N,N-dimethyl-acetamide hydrochloride in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C 34
H
42
N
7 0 3
CI
2 [(M+H)*] 20 666.2721, observed 666.2721.
WO 2007/082805 PCT/EP2007/050136 - 36 Example 22 cis-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-p~henyl)-4,5-dihydro 5 imidazol-1-yll-[4-(2-methanesulfonyl-ethyl)-piperazin-1-vll-methanone hydrochloride Ci NH N O SN>_N \ H -O N ci O1 CIH cis--4-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5 dihydro-imidazole-1-carbonyl chloride (example 20) was reacted with 1-(2 10 methanesulfonyl-ethyl)piperazine dihydrochloride (example 3) to give cis-[2-(2-tert butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl] [4-(2-methanesulfonyl-ethyl)-piperazin-1 -yl]-methanone hydrochloride in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for
C
33
H
4 1
N
6 04SC1 2 [(M+H)*] 687.2282, observed 687.2286. 15 Example 23 cis-2-{4-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-p~henyl)-4,5 dihydro-imidazole-1 -carbonyll-piperazin-1 -yl}-1 -morpholin-4-yl-ethanone H O N -N N O NO 20 WO 2007/082805 PCT/EP2007/050136 - 37 cis-4-[2-(2-tert-Butyl-4-ethoxy-pyri midi n-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-di hydro imidazole-1 -carbonyl chloride (example 20) was reacted with 1 -morpholin-4-yl-2 piperazin-1 -yl-ethanone (Oakwood Products) to give cis-2-{4-[2-(2-tert-butyl-4 ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1 -carbonyl] 5 piperazin-1-yl}-1-morpholin-4-yl-ethanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C3 6
H
44
N
7 0 4
CI
2 [(M+H)*] 708.2827, observed 708.2830. Example 24 10 cis-[2-(2-tert-Butyl-4-ethoxy-pvrimidin-5-vl)-4,5-bis-(4-chloro-p~henyl)-4,5-dihydro imidazol-1 -vll-(4-dimethylamino-piperidin-1 -l)-methanone CI H O N N CI
-
H -O N cis-4-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro 15 imidazole-1-carbonyl chloride (example 20) was reacted 4-dimethylamino piperidine (Aldrich) to give cis-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4 chloro-phenyl)-4,5-dihydro-imidazol-1 -yl]-(4-dimethylamino-piperidin-1 -yl) methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C 33
H
41
N
6 02CI 2 [(M+H)*] 623.2663, observed 623.2665.
WO 2007/082805 PCT/EP2007/050136 - 38 Example 25 cis-[2-(2-tert-Butyl-4-ethoxy-pvrimidin-5-vl)-4,5-bis-(4-chloro-p~henyl)-4,5-dihydro 5 imidazol-1-vll-(4-pyrrolidin-1-vl-piperidin-1-vl)-methanone C1 H O N -N ,\ N N Cl .- H -O Q cis-4-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazole-1-carbonyl chloride (example 20) was reacted with 4-pyrrolidin-1-yl piperidine (Aldrich) to give cis-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4 10 chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl) methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C3 5
H
42
N
6 02CI 2 [(M+H)*] 649.2819, observed 649.2822. Example 26 15 cis-1 -{4-[2-(2-tert-Butyl-4-ethoxy-pvrimidin-5-vl)-4,5-bis-(4-chloro-p~henyl)-4,5 dihydro-imidazole-1 -carbonyll-ipiiperazin-1 -yll-ethanone C1 H O N N ~N N Cl
-
H -O cis-4-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro 20 imidazole-1-carbonyl chloride (example 20) was reacted with 1-acetyl-piperazine (Aldrich) to give cis-1-{4-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro phenyl)-4,5-dihydro-imidazole-1 -carbonyl]-piperazin-1 -yl}-ethanone in an WO 2007/082805 PCT/EP2007/050136 - 39 analogous manner as described in example 1. HR-MS (ES, m/z) calculated for
C
32
H
37
N
6 03CI 2 [(M+H)*] 623.2299, observed 623.2303. Example 27 5 cis-[2-(2-tert-Butyl-4-ethoxy-pvrimidin-5-vl)-4,5-bis-(4-chloro-p~henyl)-4,5-dihydro imidazol-1 -yll-(4-methyl-piperazin-1 -l)-methanone C1 H O N N ~N N Cl .- H O cis-4-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro 10 imidazole-1-carbonyl chloride (example 20) was reacted with 1-methyl-piperazine (Aldrich) to give cis-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for
C
32
H
37
N
6 02CI 2 [(M+H)*] 595.2350, observed 595.2351. 15 Example 28 cis-[2-(2-tert-Butyl-4-ethoxy-pvrimidin-5-vl)-4,5-bis-(4-chloro-p~henyl)-4,5-dihydro imidazol-1 -vll-[4-(3-methanesulfonyl-propyl)-piperazin-1 -yll-methanone C1 H O N - -N r N 0 N 20 1-(3-Methanesulfonyl-propyl)-piperazine dihydrochloride was prepared from 1 -tert butyloxycarbonyl-piperazine and methanesulfonic acid 3-methanesulfonyl-propyl WO 2007/082805 PCT/EP2007/050136 - 40 ester (prepared according to Baerlocher, F.J. et al. Aust. J. Chem. 1999, 52, 167 172) in an analogous manner as described for the preparation of N-(2-methoxy-1 methyl-ethyl)-2-piperazin-1 -yl-acetamide dihydrochloride (example 40). 5 cis-4-[2-(2-tert-Butyl-4-ethoxy-pyri midi n-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-di hydro imidazole-1-carbonyl chloride (example 20) was reacted with 1-(3 methanesulfonyl-propyl)-piperazine dihydrochloride to give cis-[2-(2-tert-butyl-4 ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1 -yl]-[4-(3 methanesulfonyl-propyl)-piperazin-1-yl]-methanone in an analogous manner as 10 described in example 1. HR-MS (ES, m/z) calculated for C 34
H
43
N
6 04SC1 2 [(M+H)*] 701.2438, observed 701.2439. Example 29 15 cis-[2-(2-tert-Butyl-4-ethoxy-pvrimidin-5-vl)-4,5-bis-(4-chloro-p~henyl)-4,5-dihydro imidazol-1 -vll-[4-(2-hydroxy-ethyl)-pip~erazin-1 -yll-methanone H O N -N N N CI ..- H O (-N N HO cis-4-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazole-1-carbonyl chloride (example 20) was reacted with 2-piperazine-1-yl 20 ethanol (Aldrich) to give cis-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4 chloro-phenyl)-4,5-dihydro-imidazol-1 -yl]-[4-(2-hydroxy-ethyl)-piperazin-1 -yl] methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C 32
H
39
N
6 03CI 2 [(M+H)*] 625.2455, observed 625.2457.
WO 2007/082805 PCT/EP2007/050136 - 41 Example 30 2-{4-[(4S,5R)-2-(2-tert-Butyl-4-ethoxy-pvrimidin-5-vl)-4,5-bis-(4-chloro-phenyl)-4,5 5 dihvdro-imidazole-1 -carbonyll-piperazin-1 -yl}-1 -morpholin-4-vl-ethanone Chiral CI H N
-N*
1 N N CI ..... H -O N O O The enantiomers of cis-2-{4-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4 chloro-phenyl)-4,5-dihydro-imidazole-1 -carbonyl]-piperazin-1 -yl}-1 -morpholin-4-yl 10 ethanone (example 23) were separated by chiral chromatography using a ChiralPak OD column. Eluent: 60% ethanol in hexane. The first peak coming off the column is the desired enantiomer, 2-{4-[(4S,5R)-2-(2-tert-butyl-4-ethoxy pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1 -carbonyl] piperazin-1-yl}-1-morpholin-4-yl-ethanone. LR-MS: 708.0 [(M+H)*] 15 Example 31 4-[(4S,5R)-2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-vl)-4,5-bis-(4-chloro-phenyl)-4,5 dihydro-imidazole-1 -carbonyll-piperazin-2-one C I Chiral H O N N H -O CI N 20 0 WO 2007/082805 PCT/EP2007/050136 - 42 The enantiomers of cis-4-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one (example 20) were separated by chiral chromatography using a ChiralPak OD column. Eluent: 60% ethanol in hexane. The first peak coming off the column is the desired enantiomer, 5 4-[(4S,5R)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5 dihydro-imidazole-1-carbonyl]-piperazin-2-one. LR-MS: 595.2 [(M+H)*] Example 32 10 cis-4-[4,5-Bis-(4-chloro-iphenyl)-2-(4,6-diethoxy-pyridin-3-yl)-4,5-dihydro-imidazole 1-carbonyll-piperazin-2-one hydrochloride CI H N0 CN H N N CIH 0 2,4-Diethoxy-5-carbethoxypyridine (prepared from 2,4-dichloro-5 15 carbethoxypyridine and sodium ethoxy using the procedure described by Nesnow, S. et al. J. Med. Chem. 1973, 16, 524) was reacted with meso-1,2-bis-(4 chlorophenyl)-ethane-1,2-diamine in an analogous manner as described in example 1 to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4,6-diethoxy-pyridin-3-yl)-4,5 dihydro-1 H-imidazole. 20 Using the procedure as described in example 1, cis-4-[4,5-bis-(4-chloro-phenyl)-2 (4,6-diethoxy-pyridin-3-yl)-4,5-dihydro-1 H-imidazole was reacted with phosgene to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4,6-diethoxy-pyridin-3-yl)-4,5-dihydro imidazole-1-carbonyl chloride. The carbonyl chloride was then coupled with 2 25 piperazinone (Alfa) to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4,6-diethoxy-pyridin 3-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one hydrochloride.
WO 2007/082805 PCT/EP2007/050136 - 43 Example 33 cis-[4,5-Bis-(4-chloro-phenyl)-2-(4,6-diethoxy-pyridin-3-yl)-4,5-dihydro-imidazol-1 5 yll-[4-(2-hydroxy-ethyl)-piperazin-1-vll-methanone hydrochloride CC HN0 Cl ~N0 r) CI H HO cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4,6-diethoxy-pyridin-3-yl)-4,5-dihydro-imidazole 1 -carbonyl chloride (example 32) was reacted with 2-piperazine-1 -yl-ethanol (Aldrich) to give cis-[4,5-bis-(4-chloro-phenyl)-2-(4,6-diethoxy-pyridin-3-yl)-4,5 10 dihydro-imidazol-1-yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone hydrochloride in an analogous manner as described in example 1. Example 34 15 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-p~henyl)-2-(3-ethoxy-thiop~hen-2-yl)-4,5-dihydro imidazole-1-carbonyll-piperazin-1-yl}-N-tert-butyl-acetamide CI H 0 Chiral N H N S N 0X N- tert-butyl-2-piperazi n-1 -yl-acetamide di hydrochloride was prepared from 1-tert 20 butyloxycarbonyl-piperazine, chloroacetylchloride and N-tert-butylamine in an WO 2007/082805 PCT/EP2007/050136 - 44 analogous manner as described for the preparation of N-(2-methoxy-1 -methyl ethyl)-2-piperazin-1-yl-acetamide dihydrochloride (example 40). 3- Ethoxy-thiophene-2-carboxylic acid ethyl ester (prepared from 3-hydroxy 5 thiophene-2-carboxylic acid) was reacted with meso-1,2-bis-(4-chlorophenyl) ethane-1 ,2-diamine in an analogous manner as described in example 1 to give cis 4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-1 H-imidazole. Using the procedure as described in example 1, cis-4,5-bis-(4-chloro-phenyl)-2-(3 10 ethoxy-thiophen-2-yl)-4,5-dihydro-1 H-imidazole was reacted with phosgene to give cis-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1 carbonyl chloride. The enantiomers of cis-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride were separated by chiral chromatography using a Modcol spring column (50 mm x 70 cm) packed with R,R 15 Whelk-01 spherical Kromasil silica gel (Regis Technologies, eluent: 30% methylene chloride in hexane, flowrate: 85 mL/min) to give the desired 2-{4 [(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1-carbonyl chloride. 20 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1-carbonyl chloride was reacted with N-tert-butyl-2-piperazin-1 -yl acetamide dihydrochloride to give 2-{4-[(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3 ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1 -yl}-N-tert butyl-acetamide in an analogous manner as described in example 1. LR-MS: 25 642.3 [(M+H)*] WO 2007/082805 PCT/EP2007/050136 - 45 Example 35 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-vl)-4,5-dihydro 5 imidazole-l-carbonyll-piperazin-1-vl-acetamide CI CH Chiral N N S H CI N
H
2 N 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1-carbonyl chloride (example 34) was reacted with 2-piperazin-1-yl 10 acetamide hydrochloride (Matrix) to give 2-{4-[(4S,5R)-4,5-bis-(4-chloro-phenyl)-2 (3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1 -carbonyl]-piperazin-1-yl} acetamide in an analogous manner as described in example 1. LR-MS: 586.2 [(M+H)*] 15 Example 36 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-vl)-4,5-dihydro imidazole-1 -carbonyll-piperazin-1 -vl}-NN-bis-(2-methoxy-ethyl)-acetamide CI H Chiral N S H N 20N 20/ WO 2007/082805 PCT/EP2007/050136 - 46 N,N-Bis-(2-methoxy-ethyl)-2-piperazin-1 -yl-acetamide dihydrochloride was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and N,N bis-(2-methoxy-ethyl)amine in an analogous manner as described for the preparation of N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide 5 dihydrochloride (example 40). 2--{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1-carbonyl chloride (example 34) was reacted with NN-bis-(2-methoxy ethyl)-2-piperazin-1-yl-acetamide dihydrochloride to give 2-{4-[(4S,5R)-4,5-bis-(4 10 chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1 -carbonyl] piperazin-1-yl}-N,N-bis-(2-methoxy-ethyl)-acetamide in an analogous manner as described in example 1. LR-MS: 702.3 [(M+H)*] Example 37 15 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-vl)-4,5-dihydro imidazole-1 -carbonyll-piperazin-1 -vl}-N-methoxy-N-methyl-acetamide CI HChiral IH 0 N N S H C I NN 0 0 20 N- Methoxy-N-methyl-2-piperazi n-1 -yl-acetamide dihydrochloride was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and N-methoxy-N methylamine in an analogous manner as described for the preparation of N-(2 methoxy-1 -methyl-ethyl)-2-piperazin-1-yl-acetamide dihydrochloride (example 40). 25 2--{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1-carbonyl chloride (example 34) was reacted with N-methoxy-N methyl-2-piperazin-1-yl-acetamide dihydrochloride to give 2-{4-[(4S,5R)-4,5-bis-(4 chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1 -carbonyl]- WO 2007/082805 PCT/EP2007/050136 - 47 piperazin-1-yl}-N-methoxy-N-methyl-acetamide in an analogous manner as described in example 1. LR-MS: 630.3 [(M+H)*]. Example 38 5 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-vl)-4,5-dihydro imidazole-1 -carbonyll-piperazin-1 -vl}-N-isopropvl-N-methyl-acetamide CI Chiral H HN C I o N N 10 N- Isopropyl-N-methyl-2-piperazin-1 -yl-acetamide dihydrochloride was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and N-isopropyl-N methylamine in an analogous manner as described for the preparation of N-(2 methoxy-1 -methyl-ethyl)-2-piperazin-1 -yl-acetamide dihydrochloride (example 40). 15 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1-carbonyl chloride (example 34) was reacted with N-isopropyl-N methyl-2-piperazin-1-yl-acetamide dihydrochloride to give 2-{4-[(4S,5R)-4,5-bis-(4 chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1 -carbonyl] piperazin-1-yl}-N-isopropyl-N-methyl-acetamide in an analogous manner as 20 described in example 1. LR-MS: 642.3 [(M+H)*].
WO 2007/082805 PCT/EP2007/050136 - 48 Example 39 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-vl)-4,5-dihydro 5 imidazole-1-carbonyll-piperazin-1-vl}-N-(2-cyano-ethyl)-N-methyl-acetamide Ci Chiral N H N0 ci o NJ N-(2-Cyano-ethyl)-N-methyl-2-piperazin-1 -yl-acetamide dihydrochloride was 10 prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and N-(2 cyanoethyl)-N-methylamine in an analogous manner as described for the preparation of N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide dihydrochloride (example 40). 15 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1-carbonyl chloride (example 34) was reacted with N-(2-cyano-ethyl)-N methyl-2-piperazin-1-yl-acetamide dihydrochloride to give 2-{4-[(4S,5R)-4,5-bis-(4 chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1 -carbonyl] piperazin-1-yl}-N-(2-cyano-ethyl)-N-methyl-acetamide in an analogous manner as 20 described in example 1. LR-MS: 653.2 [(M+H)*].
WO 2007/082805 PCT/EP2007/050136 - 49 Example 40 cis-2-{4-[4,5-Bis-(4-chloro-p~henvl)-2-(3-ethoxy-thiop~hen-2-vl)-4,5-dihydro 5 imidazole-1-carbonyll-piperazin-1-vl}-N-(2-methoxy-1-methyl-ethyl)-acetamide CI H N ci o N IH 0 0-. 2-Methoxy-1-methyl-ethylamine (15 mmol, 1.15 eq) and diisopropylethylamine (17 mmol, 1.3 eq) were diluted with methylene chloride to give a total volume of 8 mL. The amine solution was added in a portion-wise fashion via a syringe to a solution 10 of chloroacetyl chloride (13 mmol) in methylene chloride (10 mL) cooled to approximately -400C in a sealed 40 mL vial. The reaction mixture was stirred for 1 h at reduced temperature. The solution was then made acidic with 1 N hydrochloric acid and then diluted with 10 mL of methylene chloride. The vial was agitated and centrifuged. The organic layer was transferred to 40 mL vials and concentrated in 15 vacuo. The residue (1.69 g, 10.21 mmol) was diluted with 10 mL of dimethylformamide. Piperazine-1-carboxylic acid tert-butyl ester (8.67 mmol, 0.85 eq) and diisopropylethylamine (13.27 mmol, 1.3 eq) were added. The reaction mixture was shaken at 65 OC overnight and concentrated in vacuo. The crude residue was dissolved in 10 mL of dioxane and 10 mL of 4M hydrochloric acid in 20 dioxane. The solution was shaken overnight at room temperature then centrifuged. The supernatant was removed, and the remaining solids were shaken with hexane then centrifuged. The supernatant was removed, and the solids was collected and 25 dried in vacuo to give N-(2-methoxy-1-methylethyl)-2-piperazin-1-yl-acetamide dihydrochloride. LR-MS: 216.4 [(M+H)*].
WO 2007/082805 PCT/EP2007/050136 - 50 2-{4-[(4S,5 R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-di hydro imidazole-1-carbonyl chloride (example 34) was reacted with N-(2-methoxy-1 methylethyl)-2-piperazin-1 -yl-acetamide dihydrochloride to give cis-2-{4-[4,5-bis (4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1 -carbonyl] 5 piperazin-1-yl}-N-(2-methoxy-1-methyl-ethyl)-acetamide in an analogous manner as described in example 1. LR-MS: 658.2 [(M+H)*]. Example 41 10 [(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiolphen-2-vl)-4,5-dihvdro-imidazol 1 -vll-[4-(3,5-dimethyl-isoxazole-4-carbonyl)-piperazin-1 -vll-methanone CI Chiral H N S !H , N/\ O CI oQ o-N A solution of 1-tert-butyloxycarbonyl-piperazine (4.581 mmol, 0.9 eq) and diisopropylethylamine (5.09 mmol, 1.0 eq) in methylene chloride (5 mL) was added 15 to a 40 mL vial. 3,5-Dimethyl-isoxazole-4-carbony chloride (5.09 mmol, 1.0 eq) was added to the vial and the reaction was shaken overnight at room temperature. When the reaction was complete, it was diluted with methylene chloride (5 mL) and washed with 4 mL of 1 N hydrochloric acid followed by 4 mL of 10% potassium carbonate. The organic layer was concentrated in vacuo. The crude residue was 20 dissolved in 5 mL of dioxane and 5 mL of 4M hydrochloric acid in dioxane. The reaction mixture was shaken overnight at room temperature then centrifuged. The supernatant was removed and the remaining solid was shaken with hexane then centrifuged. The supernatant was removed, and the solids were collected and dried in vacuo to give (3,5-dimethyl-isoxazol-4-yl)-piperazin-1 -yl-methanone. LR 25 MS: 210.2 [(M+H)*]. 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1-carbonyl chloride (example 34) was reacted with (3,5-dimethyl isoxazol-4-yl)-piperazin-1 -yl-methanone to give [(4S,5R)-4,5-bis-(4-chloro-phenyl)- WO 2007/082805 PCT/EP2007/050136 -51 2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazol-1 -yl]-[4-(3,5-dimethyl-isoxazole-4 carbonyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. LR-MS: 652.2 [(M+H)*]. 5 Example 42 [(4S,5R)-4,5-Bis-(4-chloro-p~henyl)-2-(3-ethoxy-thiop~hen-2-yl)-4,5-dihydro-imidazol 1 -yll-(4-ethanesulfonyl-piperazin-1 -yl)-methanone CI /C Chiral HN0 N S H 0 10 Ethanesulfonyl-piperazine was prepared from 1 -tert-butyloxycarbonyl-piperazine and ethylsulfonyl chloride in an analogous manner as described for the preparation of (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone in example 41. 15 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1-carbonyl chloride (example 34) was reacted with 1-ethanesulfonyl piperazine to give [(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl) 4,5-dihydro-imidazol-1-yl]-(4-ethanesulfonyl-piperazin-1-yl)-methanone in an analogous manner as described in example 1. LR-MS: 621.2 [(M+H)*] WO 2007/082805 PCT/EP2007/050136 - 52 Example 43 N-(2-{4-[(4S,5R)-4,5-Bis-(4-chloro-p~henyl)-2-(3-ethoxy-thiop~hen-2-vl)-4,5-dihydro 5 imidazole-1-carbonyll-piperazin-1-vl}-ethyl)-methanesulfonamide CI Chiral IH 0 N H N S I o H N % 0 Methanesulfonyl chloride (0.7 mL, 9.0 mmol) was added to a cooled solution of 4 (2-amino-ethyl)-piperazine-1 -carboxylic acid tert-butyl ester (1.33 g, 5.8 mmol) in pyridine (25.0 mL). The reaction was stirred for 12 h and partitioned between 10 partitioned between aqueous sodium bicarbonate and methylene chloride. The organic phase was washed with 1 M hydrochloric acid, aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate and concentrated. Purification of the crude residue by flash chromatography over silica gel using 0 5% methanol in methylene chloride gave 4-(2-methanesulfonylamino-ethyl) 15 piperazine-1-carboxylic acid tert-butyl ester (0.70 g, 70%). To a cooled solution of 4-(2-methanesulfonylamino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.64 g, 0.2 mmol) in dioxane (20 mL) was added hydrochloric acid (4M in dioxane, 10 mL) and the reaction was stirred at room temperature for 20 12 h and concentrated to give N-(2-methanosulfonylethyl)-piperazine dihydrochloride as a white solid (0.55 g, 95%). 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1-carbonyl chloride (example 34) was reacted with N-(2 25 methanosulfonylethyl)-piperazine dihydrochloride to give N-(2-{4-[(4S,5R)-4,5-bis (4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1 -carbonyl] piperazin-1 -yl}-ethyl)-methanesulfonamide in an analogous manner as described in example 1. LR-MS: 650.1 [(M+H)*].
WO 2007/082805 PCT/EP2007/050136 - 53 Example 44 [(4S,5R)-4,5-Bis-(4-chloro-p~henyl)-2-(3-ethoxy-thiop~hen-2-vl)-4,5-dihydro-imidazol 5 1 -vll-[4-(3-methanesulfonyl-propyl)-piperazin-1 -yll-methanone CH- Chiral HN0 N S H 0-- CI 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1-carbonyl chloride (example 34) was reacted with 1-(3 10 methanesulfonyl-propyl)-piperazine dihydrochloride (example 28) to give [(4S,5R) 4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazol-1 -yl]-[4 (3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. LR-MS: 649.2 [(M+H)*]. 15 Example 45 [(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazol 1 -vll-[4-(2-methanesulfonyl-ethyl)-piperazin-1 -yll-methanone CI Chiral H 0 H 0 20 V 0 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1-carbonyl chloride was reacted with 1-(2- WO 2007/082805 PCT/EP2007/050136 - 54 methanesulfonylethyl)piperazine dihydrochloride (example 3) to give [(4S,5R)-4,5 bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazol-1 -yl]-[4-(2 methanesulfonyl-ethyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. LR-MS: 635.1 [(M+H)*]. 5 Example 46 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1 -carbonyll-piperazin-1 -yl}-1 -morpholin-4-yl-ethanone CI Chiral N S HN CI oQ Cl 0 10 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro imidazole-1 -carbonyl chloride (example 28) was reacted with 1 -morpholin-4-yl-2 piperazin-1 -yl-ethanone (Oakwood Products) to give 2-{4-[(4S,5R)-4,5-bis-(4 chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1 -carbonyl] 15 piperazin-1-yl}-1-morpholin-4-yl-ethanone in an analogous manner as described in example 1. LR-MS: 656.3 [(M+H)*]. Example 47 20 In Vitro Activity Assay The ability of the compounds to inhibit the interaction between p53 and MDM2 proteins was measured by an HTRF (homogeneous time-resolved fluorescence) assay in which recombinant GST-tagged MDM2 binds to a peptide that resembles the MDM2-interacting region of p53 (Lane et al.). Binding of GST-MDM2 protein 25 and p53-peptide (biotinylated on its N-terminal end) is registered by the FRET (fluorescence resonance energy transfer) between Europium (Eu)-labeled anti GST antibody and streptavidi n-conjugated Allophycocyanin (APC).
- 55 Test is performed in black flat-bottom 384-well plates (Costar) in a total volume of 40 uL containing:90 nM biotinylate peptide, 160 ng/mL GST-MDM2, 20 nM streptavidin-APC (PerkinElmerWallac), 2 nM Eu-labeled anti-GST-antibody (PerkinElmerWallac), 0.2% bovine serum albumin (BSA), 1 mM dithiothreitol (DTT) and 20 mM Tris-borate saline 5 (TBS) buffer as follows: Add 10 uL of GST-MDM2 (640 ng/mL working solution) in reaction buffer to each well. Add 10 uL diluted compounds (1:5 dilution in reaction buffer) to each well, mix by shaking. Add 20 uL biotinylated p53 peptide (180 nM working solution) in reaction buffer to each well and mix on shaker. Incubate at 37 0 C for 1 h. Add 20 uL streptavidin-APC and Eu-anti-GST antibody mixture (6 nM Eu-anti-GST and 60 nM 10 streptavidin-APC working solution) in TBS buffer with 0.2% BSA, shake at room temperature for 30 minutes and read using a TRF-capable plate reader at 665 and 615 nm (Victor 5, Perkin ElmerWallac). If not specified, the reagents were purchased from Sigma Chemical Co. 15 IC50s showing biological activity that applies to compounds of the subject matter of this invention ranges from about 0.030 uM to about 7 uM. Specific data for some examples are as follows: Example
IC
50 (pM) 6 2.890 17 0.677 20 0.046 34 0.110 36 0.054 Throughout this specification and the claims which follow, unless the context requires 20 otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), 25 or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims (15)

  1. 04.10.2007 Claims The compound of formula I VI H N N 5 4 Ring A N HO V 2 and the pharmaceutically acceptable salts and esters thereof, wherein Ring A is xiS X1 Z Y zY X 2 wherein X, is ethoxy; X 2 is hydrogen, -O-(CI-C6)alkyl, -S-(C1-C6)alkyl, -(Cl-C6)alkyl, or AMENDED SHEET 10/10/2007 WO 2007/082805 PCT/EP/2007/050136 Amended page 57 -CF 3 , and Z and Y are both nitrogen; V 1 and V 2 are -Cl; R is N R, N (CH 2 )n wherein R 1 is oxo, -C(O)-(C1-6)alkyl, -C(O)-dimethyl isoxazole, -S(O) 2 -(C1-C6)alkyl, or -(C1-C6)alkyl, which is unsubstituted or once substituted by -OH, -S(O) 2 -(C1-C6)alkyl, -C(O)-morpholino, -C(O)-N[(C1-C6)alkyl] 2 , wherein each alkyl independently is unsubstituted or once substituted by cyano or methoxy, -C(O)-NH-(C1-C6)alkyl, wherein the alkyl is unsubstituted or once substituted by methoxy, AMENDED SHEET 10/10/2007 WO 2007/082805 PCT/EP/2007/050136 Amended page 58 -C(O)-NH 2 , -C(O)-N(C1-C4alkyl)(CI-C4alkoxy), or -NH-S(O) 2 -(C1-C6)alkyl, and n = 1; and pharmaceutically acceptable salts thereof. 2. The compound of claim 1 wherein the two hydrogen of the imidazoline ring are in the cis configuration to each other. 3. A compound selected from the group consisting of :is-4-[(4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-y)-4,5-dihydro-imidazole- 1 :arbonyl]-piperazin-2-one, :is-2-{4-[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1 :arbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide, :is-[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazol-1 -yl]-[4-(2 -nethanesulfonyl-ethyl)-piperazin-1 -yi]-methanone, :is-2-{4-[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-y)-4,5-dihydro-imidazole-1 :arbonyl]-piperazin-1 -yl}-1 -morpholin-4-yl-ethanone, AMENDED SHEET 10/10/2007 WO 2007/082805 PCT/EP/2007/050136 Amended page 59 cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro imidazole-l-carbonyl]-piperazin-2-one, cis-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro imidazol-1 -yI]-[4-(2-methanesulfonyl-ethyl)-piperazin-1 -yl]-methanone, cis-2-{4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyri midin-5-yl)-4,5 dihydro-imidazole-1 -carbonyl]-piperazin-1 -yl}-1 -morpholin-4-yl-ethanone, cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro-imidazole- 1 carbonyl]-piperazin-2-one, cis-2-{4-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro-imidazole 1 -carbonyl]-piperazin-1 -yl}-N,N-dimethyl-acetamide, cis-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-y)-4,5-dihydro-imidazol-1 -yl] [4-(2-methanesulfony-ethyl)-piperazin-1 -yl]-methanone, cis-2-{4-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-y)-4,5-dihydro-imidazole 1 -carbonyl]-piperazin-1 -yl}-1 -morpholin-4-yi-ethanone, cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfany-pyrimidin-5-yl)-4,5-dihydro imidazole-1-carbonyl]-piperazin-2-one and cis-2-{4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfany-pyrimidin-5-yl)-4,5 dihydro-imidazole-1 -carbonyl]-piperazin-1 -yl}-N,N-dimethyl-acetamide. 4. A compound selected from the group consisting of cis-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro imidazol-1 -yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1 -yl]-methanone, cis-2-{4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidi n-5-yl)-4,5 dihydro-imidazole-1 -carbonyl]-piperazin-1 -yl}-1 -morpholin-4-yl-ethanone, AMENDED SHEET 10/10/2007 WO 2007/082805 PCT/EP/2007/050136 Amended page 60 cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-y)-4,5-dihydro imidazole-1 -carbonyl]-piperazin-2-one, cis-2-{4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyimidin-5-yl)-4,5-dihydro imidazole-1 -carbonyl]-piperazin-1 -yl}-N,N-dimethyl-acetamide, cis-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-y)-4,5-dihydro-imidazol 1 -yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1 -yl]-methanone, cis-2-{4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-y)-4,5-dihydro imidazole-1 -carbonyl]-piperazin-1 -yl}-1 -morpholin-4-yl-ethanone, cis-4-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yi)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazole-1-carbonyl]-piperazin-2-one hydrochloride, cis-2-{4-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazole-1-carbonyl]-piperazin-1-yI}-N,N-dimethyl-acetamide hydrochloride, cis-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride, cis-2-{4-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazole-1 -carbonyl]-piperazin-1 -yl}-1 -morpholin-4-yl-ethanone, cis-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazol-1 -yl]-(4-dimethylamino-piperidin-1 -yl)-methanone, cis-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazol-1 -yl]-(4-pyrrolidin-1 -yl-piperidin-1 -yl)-methanone and cis-1 -{4-[2-(2-tert-Butyl-4-ethoxy-pyri midin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro midazole-1 -carbonyl]-piperazin-1 -yl}-ethanone.
  2. 5. A compound selected from the group consisting of AMENDED SHEET 10/10/2007 WO 2007/082805 PCT/EP/2007/050136 Amended page 61 cis-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro midazol-1 -yl]-(4-methyl-piperazin-1 -yl)-methanone, cis-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-y)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro midazol-1 -yl]-[4-(3-methanesulfony-propyl)-piperazin-1 -yl]-methanone, cis-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro midazol-1 -yl]-[4-(2-hyd roxy-ethyl)-piperazin-1 -yl]-methanone, 2-{4-[(4S,5R)-2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5 lihydro-imidazole-1 -carbonyl]-piperazin-1 -yl}-1 -morpholin-4-yl-ethanone, 4-[(4S,5R)-2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-y)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro midazole-1 -carbonyl]-piperazin-2-one, ,is-4-[4,5-Bis-(4-chloro-phenyl)-2-(4,6-diethoxy-pyridin-3-yl)-4,5-dihydro-imidazole- 1 :arbonyl]-piperazin-2-one hydrochloride, ,is-[4,5-Bis-(4-chloro-phenyl)-2-(4,6-diethoxy-pyridin-3-yl)-4,5-dihydro-imidazol-1-yI]-[4 2-hydroxy-ethyl)-piperazin-1-yl]-methanone hydrochloride, 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro midazole-1-carbonyl]-piperazin-1-yl}-N-tert-butyl-acetamide, 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro midazole-1-carbonyl]-piperazin-1-yI}-acetamide, 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro midazole-1-carbonyl]-piperazin-1-yl}-N,N-bis-(2-methoxy-ethyl)-acetamide, 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro midazole-1 -carbonyl]-piperazin-1 -yl}-N-methoxy-N-methyl-acetamide, 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro midazole-1-carbonyl]-piperazin-1 -yl}-N-isopropyl-N-methyl-acetamide, 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro midazole-1 -carbonyl]-piperazin-1 -yl}-N-(2-cyano-ethyl)-N-methyl-acetamide, AMENDED SHEET 10/10/2007 WO 2007/082805 PCT/EP/2007/050136 Amended page 62 cis-2-{4-[4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1 carbonyl]-piperazin-1-yl}-N-(2-methoxy-1-methyl-ethyl)-acetamide and [(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazol-1 -yl] [4-(3,5-dimethyl-isoxazole-4-carbonyl)-piperazin-1 -yl]-methanone.
  3. 6. A compound selected from the group consisting of [(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-y)-4,5-dihydro-imidazol-1 -yl] (4-ethanesulfony-piperazin-1 -yl)-methanone, N-(2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro midazole-1-carbonyl]-piperazin-1 -yl}-ethyl)-methanesulfonamide, (4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-y)-4,5-dihydro-imidazol-1 -yl] [4-(3-methanesulfony-propyl)-piperazin-1-yl]-methanone, (4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-y)-4,5-dihydro-imidazol-1 -yl] [4-(2-methanesulfony-ethyl)-piperazin-1-yl]-methanone and 2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro midazole-1 -carbonyl]-piperazin-1 -yl}- 1 -morpholin-4-y-ethanone.
  4. 7. A pharmaceutical composition comprising a compound of the formula I according o claim 1 and a pharmaceutically acceptable carrier.
  5. 8. The process for the manufacture of the compounds of claim 1, wherein a) a compound of the formula 3 AMENDED SHEET 10/10/2007 WO 2007/082805 PCT/EP/2007/050136 Amended page 63 v, H N \>-Ring A N H H V 2 3 is reacted with phosgene in the presence of a base such as triethylamine to give a racemic carbamoyl chloride of the formula 4 v, H N >-Ring A N I H V 2 Ci b) the racemic carbamoyl chloride of the formula 4 is further reacted with an R amine to give the respective compound of the formula I as racemic mixture, and c) said racemic mixture is separated by chiral chromatography to give the specific enantiomers of formula I; wherein V1, V 2 , R and the Ring A have the meanings given in claim 1. AMENDED SHEET 10/10/2007 - 64 9. A compound of the formula I as defined in claim 1, substantially as hereinbefore described with reference to the Examples.
  6. 10. A compound according to claim 1 when used as a medicament. 5
  7. 11. A compound according to claim 1 when used for the treatment of cancer.
  8. 12. The compound when used according to claim 11 wherein the cancer is a solid tumor. 10
  9. 13. The compound when used according to claim 12 wherein the solid tumor is a breast, colon, lung or prostate tumor.
  10. 14. The use of a compound according to claim 1 in the manufacture of a medicament 15 for the treatment of cancer.
  11. 15. The use of claim 14 wherein the cancer is a solid tumor.
  12. 16. The use according to claim 15 wherein the solid tumor is a breast, colon, lung or 20 prostate tumor.
  13. 17. A method for the treatment of cancer in a subject in need thereof said method comprising administration to the subject of a therapeutically effective amount of a compound according to claim 1. 25
  14. 18. The method according to claim 17 wherein the cancer is a solid tumor.
  15. 19. The method according to claim 18 wherein the solid tumor is a breast, colon, lung or prostate tumor.
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